7-azaindoles and the use thereof as therapeutic agents

ABSTRACT

The invention relates to substituted 7-azaindoles, process for their preparation, pharmaceutical preparations which comprise these compounds, and the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 4, as active ingredients for the treatment of disorders which can be influenced by inhibition of phosphodiesterase 4 activity in particular in immunocompetent cells (e.g. macrophages and lymphocytes) by the compounds of the invention.

[0001] The invention relates to substituted 7-azaindoles, process fortheir preparation, pharmaceutical preparations which comprise thesecompounds, and the pharmaceutical use of these compounds, which areinhibitors of phosphodiesterase 4, as active ingredients for thetreatment of disorders which can be influenced by inhibition ofphosphodiesterase 4 activity in particular in immunocompetent cells(e.g. macrophages and lymphocytes) by the compounds of the invention.

[0002] Activation of cell membrane receptors by transmitters leads toactivation of the second messenger system. Adenylate cyclase synthesizesthe active cyclic AMP (cAMP) and cyclic GMP (cGMP) respectively from AMPand GMP. cAMP and cGMP lead for example in smooth muscle cells torelaxation, and in inflammatory cells to inhibition of mediator releaseand synthesis. The second messengers cAMP and cGMP are degraded byphosphodiesterases (PDE). To date, 11 families of PDE enzymes (PDE1-11)are known and differ through their substrate specificity (cAMP, cGMP orboth) and the dependence on other substrates (e.g. calmodulin). Theseisoenzymes have different functions in the body and are expresseddifferently in individual cell types (Beavo, J. A., Conti, M. andHeaslip, R. J., Multiple cyclic nucleotide phosphodiesterases. Mol.Pharmacol. 1994, 46:399-405; Hall, I. P., Isoenzyme selectivephosphodiesterase inhibitors: potential clinical uses, Br. J. clin.Pharmacol. 1993, 35:1-7). Inhibition of the various PDE isoenzyme typesresults in accumulation of cAMP or cGMP in cells, which can be utilizedtherapeutically (Torphy, T. J., Livi, G. P., Christensen, S. B. NovelPhosphodiesterase Inhibitors for the Therapy of Asthma, Drug News andPerspectives 1993, 6:203-214).

[0003] The predominant PDE-isoenzyme in cells important for allergicinflammations (lymphocytes, mast cells, eosinophilic granulocytes,macrophages) is that of type 4 (Torphy, J. T. and Undem, B. J.,Phosphodiesterase inhibitors: new opportunities for the treatment ofasthma. Thorax 1991, 46:512-523). Inhibition of PDE 4 by suitableinhibitors is therefore regarded as an important approach to the therapyof a large number of allergically induced disorders (Schudt, Ch., Dent,G., Rabe, K, Phosphodiesterase Inhibitors, Academic Press London 1996).

[0004] An important property of phosphodiesterase 4 inhibitors isinhibition of the release of tumor necrosis factor α (TNFα) frominflammatory cells. TNFα is an important proinflammatory cytokine whichinfluences a large number of biological processes. TNFα is released forexample from activated macrophages, activated T lymphocytes, mast cells,basophils, fibroblasts, endothelial cells and astrocytes in the brain.It has itself an activating effect on neutrophils, eosinophils,fibroblasts and endothelial cells, whereby various tissue-damagingmediators are released. The effect of TNFα in monocytes, macrophages andT lymphocytes is increased production of further proinflammatorycytokines such as GM-CSF (granulocyte-macrophage colony-stimulatingfactor) or interleukin-8. Owing to its proinflammatory and cataboliceffect, TNFα plays a central role in a large number of disorders such asinflammations of the respiratory tract, inflammations of the joints,endotoxic shock, tissue rejections, AIDS and many other immunologicaldisorders. Thus, phosphodiesterase 4 inhibitors are likewise suitablefor the therapy of such disorders associated with TNFα.

[0005] Chronic obstructive pulmonary diseases (COPD) are widespread inthe population and also have great economic importance. Thus, COPDdisorders are the cause of about 10-15% of all illness costs in thedeveloped countries, and about 25% of all deaths in the USA areattributable to this cause (Norman, P.: COPD: New developments andtherapeutic opportunities, Drug News Perspect. 11 (7), 431-437, 1998).The WHO estimates that COPD will become the third-commonest cause ofdeath in the next 20 years.

[0006] The pathological condition of chronic obstructive pulmonarydiseases (COPD) encompasses various pathological conditions of chronicbronchitis with the symptoms of coughing and expectoration, andprogressive and irreversible deterioration in lung function (expirationis particularly affected). The course of the disease is episodic andoften complicated by bacterial infections (Rennard, S. I.: COPD:Overview of definitions, Epidemiology, and factors influencing itsdevelopment. Chest, 113 (4) Suppl., 235S-241S, 1998). There is a steadydecline in lung function during the disorder, the lung becomesincreasingly emphysematous, and the patients' breathing difficultybecomes obvious. This disorder markedly impairs the patients' quality oflife (shortness of breath, low exercise tolerance) and significantlyshortens their life expectancy. Besides environmental factors, the mainrisk factor is smoking (Kummer, F.: Asthma and COPD. Atemw.-Lungenkrkh.20 (5), 299-302, 1994; Rennard, S. I.: COPD: Overview of definitions,Epidemiology, and factors influencing its development. Chest, 113 (4)Suppl., 235S-241S, 1998) and thus men are affected distinctly morefrequently than are women. However, this picture will change in thefuture due to the alteration in lifestyles and the increase in thenumber of female smokers.

[0007] Current therapy claims only to alleviate the symptoms withoutaffecting the causes of the progression of the disorder. The use oflong-acting beta2 agonists (e.g. salmeterol), possibly in combinationwith muscarinergic antagonists (e.g. ipratropium), improves lungfunction through bronchodilatation and is routinely employed (Norman,P.: COPD: New developments and therapeutic opportunities, Drug NewsPerspect. 11 (7), 431-437, 1998). Bacterial infections play a large partin the episodes of COPD and need antibiotic treatment (Wilson, R.: Therole of infection in COPD, Chest, 113 (4) Suppl., 242S-248S, 1998;Grossman, R. F.: The value of antibiotics and the outcomes of antibiotictherapy in exacerbations of COPD. Chest, 113 (4) Suppl., 249S-255S,1998). Therapy of this disorder is currently unsatisfactory, especiallyin relation to the continuous decline in lung function. New therapeuticapproaches acting on mediators of inflammation, proteases or adhesionmolecules might be very promising (Barnes, P. J.: Chronic obstructivedisease: new opportunities for drug development, TiPS 10 (19), 415-423,1998).

[0008] Irrespective of the bacterial infections complicating thedisorder, a chronic inflammation is found in the bronchi and isdominated by neutrophilic granulocytes. The mediators and enzymesreleased by neutrophilic granulocytes are thought inter alia to beresponsible for the observed structural changes in the respiratory tract(emphysema). Inhibition of the activity of neutrophilic granulocytes isthus a rational approach to the prevention or slowing down of theprogression of COPD (deterioration in parameters of lung function). Animportant stimulus for the activation of granulocytes is theproinflammatory cytokine TNFα (tumor necrosis factor). Thus, it is knownthat TNFα stimulates the formation of oxygen free radicals byneutrophilic granulocytes (Jersmann, H. P. A.; Rathjen, D. A. andFerrante, A.: Enhancement of LPS-induced neutrophil oxygen radicalproduction by TNFα, Infection and Immunity, 4, 1744-1747, 1998). PDE4inhibitors are able to inhibit very effectively the release of TNFα froma large number of cells and thus suppress the activity of neutrophilicgranulocytes. The nonspecific PDE inhibitor pentoxifylline is able toinhibit both the formation of oxygen free radicals and the phagocyticability of neutrophilic granulocytes (Wenisch, C.; Zedtwitz-Liebenstein,K.; Parschalk, B. and Graninger, W.: Effect of pentoxifylline in vitroon neutrophil reactive oxygen production and phagocytic ability assessedby flow cytometry, Clin. Drug Invest., 13(2):99-104, 1997).

[0009] Various PDE 4 inhibitors have already been disclosed. These areprimarily xanthine derivatives, rolipram analogs or nitraquazonederivatives (review in: Karlsson, J. A., Aldos, D., Phosphodiesterase 4inhibitors for the treatment of asthma, Exp. Opin. Ther. Patents 1997,7: 989-1003). It has not been possible to date for any of thesecompounds to be used clinically. It was unavoidably found that the knownPDE4 inhibitors also have various side effects, such as nausea andemesis, which it has not to date been possible to suppress adequately.It is therefore necessary to discover novel PDE4 inhibitors withimproved therapeutic index.

[0010] Indol-3-ylglyoxylamides and processes for preparing them havealready been described several times. In all cases, indolesunsubstituted in position 3, which are synthesized by substitution inposition 1 of a commercially available indole, were converted byreaction with oxalyl halides into indol-3-ylglyoxylyl halides whichsubsequently afford, by reaction with ammonia or with primary orsecondary amines, the corresponding indol-3-ylglyoxylamides. (Scheme 1)

[0011] Thus, U.S. Pat. Nos. 2,825,734 and 3,188,313 describe variousindol-3-ylglyoxylamides which are prepared by the manner depicted inScheme 1. These compounds were used as intermediates for preparingindole derivatives produced by reductions. U.S. Pat. No. 3,642,803 alsodescribes indol-3-ylglyoxylamides.

[0012] The preparation of 5-methoxyindol-3-ylglyoxylamides is describedin Farmaco 22 (1967), 229-244. Again there is reaction of the indolederivative used with oxalyl chloride, and the resultingindol-3-ylglyoxylyl chloride is reacted with an amine.

[0013] In addition, U.S. Pat. No. 6,008,231 describesindol-3-ylglyoxylamides and processes for preparing them. Once again,the reaction steps and conditions depicted in Scheme 1 are used.

[0014] Substituted 5-hydroxyindolylglyoxylamides and6-hydroxyindolylglyoxylamides and processes for preparing them and theuse thereof as PDE4 inhibitors were described for the first time in DEpatent application 198 18 964 A1.

[0015] 7-Azaindol-3-ylglyoxylamides are disclosed as PDE4 inhibitors inDE patent application 100 53 275 A1, which also describes theirpreparation and use as therapeutic agents.

[0016] 4- and 7-Hydroxyindole derivatives, their preparation and use asPDE4 inhibitors are proposed in DE patent application 102 53 426.8.

[0017] The invention relates to substituted 7-azaindoles of the generalformula 1

[0018] and the physiologically tolerated salts thereof.

[0019] The compounds of the invention preferably include compounds ofthe formula 1 in which

[0020] A is an N-oxide group and B is carbon (i.e. a CH group or a groupCR³ as defined below) or nitrogen. These are the compounds of theinvention of the formula 1a

[0021] in which

[0022] R¹

[0023] (i) is —C₁₋₁₀-alkyl, straight-chain or branched-chain, optionallymono- or polysubstituted by —OH, —SH, —NH₂, —NHC₁₋₆-alkyl,—N(C₁₋₆-alkyl)₂, —NHC₆₋₁₄-aryl, —N(C₆₋₁₄-aryl)₂,—N(C₁₋₆-alkyl)(C₆₋₁₄-aryl), —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl,—O—C₆₋₁₄-aryl, —S—C₁₋₆-alkyl, —S—C₆₋₁₄-aryl, —SO₃H, —SO₂C₁₋₆-alkyl,—SO₂C₆₋₁₄-aryl, —OSO₂C₁₋₆-alkyl, —OSO₂C₆₋₁₄-aryl, —COOH,—(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl, —O(CO)C₁₋₅-alkyl, by mono-, bi- ortricyclic saturated or mono- or polyunsaturated carbocycles with 3-14ring members or/and by mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles with 5-15 ring members and 1-6 heteroatoms,which are preferably N, O and S, where the C₆₋₁₄-aryl groups and thecarbocyclic and heterocyclic substituents in turn may optionally besubstituted one or more times by —C₁₋₆-alkyl, —OH, —NH₂, —NHC₁₋₆-alkyl,—N(C₁₋₆-alkyl)₂, —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —SO₃H, —SO₂C₁₋₆-alkyl, —OSO₂C₁₋₆-alkyl, —COOH,—(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl or/and —O(CO)C₁₋₅-alkyl, and where thealkyl groups on the carbocyclic and heterocylic substituents in turn mayoptionally be substituted one or more times by —OH, —SH, —NH₂, —F, —Cl,—Br, —I, —SO₃H or/and —COOH, or

[0024] (ii) is —C₂₋₁₀-alkenyl, mono- or polyunsaturated, straight-chainor branched-chain, optionally mono- or polysubstituted by —OH, —SH,—NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NHC₆₋₁₄-aryl, —N(C₆₋₁₄-aryl)₂,—N(C₁₋₆-alkyl)(C₆₋₁₄-aryl), —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl,—O—C₆₋₁₄-aryl, —S—C₁₋₆-alkyl, —S—C₆₋₁₄-aryl, —SO₃H, —SO₂C₁₋₆-alkyl,—SO₂C₆₋₁₄-aryl, —OSO₂C₁₋₆-alkyl, —OSO₂C₆₋₁₄-aryl, —COOH,—(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl or/and —O(CO)C₁₋₅-alkyl, by mono-, bi-or tricyclic saturated or mono- or polyunsaturated carbocycles with 3-14ring members or/and by mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles with 5-15 ring members and 1-6 heteroatoms,which are preferably N, O and S,

[0025] where the C₆₋₁₄-aryl groups and the carbocyclic and heterocyclicsubstituents in turn may optionally be substituted one or more times by—C₁₋₆-alkyl, —OH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NO₂, —CN, —F,—Cl, —Br, —I, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —SO₃H, —SO₂C₁₋₆-alkyl,—OSO₂C₁₋₆-alkyl, —COOH, —(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl or/and—O(CO)C₁₋₅-alkyl,

[0026] and where the alkyl groups on the carbocyclic and heterocyclicsubstituents in turn may optionally be substituted one or more times by—OH, —SH, —NH₂, —F, —Cl, —Br, —I, —SO₃H or/and —COOH,

[0027] R² is hydrogen or —C₁₋₃-alkyl,

[0028] R³ and R⁴ may be identical or different and are hydrogen,—C₁₋₆-alkyl, —OH, —SH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NO₂, —CN,—SO₃H, —SO₃—C₁₋₆-alkyl, —COOH, —COO—C₁₋₆-alkyl, —O(CO)—C₁₋₅-alkyl, —F,—Cl, —Br, —I, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, -phenyl or -pyridyl, wherethe phenyl or pyridyl substituents in turn may optionally be substitutedone or more times by —C₁₋₃-alkyl, —OH, —SH, —NH₂, —NHC₁₋₃-alkyl,—N(C₁₋₃-alkyl)₂, —NO₂, —CN, —SO₃H, —SO₃C₁₋₃-alkyl, —COOH,—COOC₁₋₃-alkyl, —F, —Cl, —Br, —I, —O——C₁₋₃-alkyl, —S—C₁₋₃-alkyl, or/and—O(CO)C₁₋₃-alkyl, and where the alkyl substituents in turn mayoptionally be substituted one or more times by —OH, —SH, —NH₂, —F, —Cl,—Br, —I, —SO₃H, —SO₃C₁₋₃-alkyl, —COOH, —COOC₁₋₃-alkyl, —O—C₁₋₃-alkyl,—S—C₁₋₃-alkyl or/and —O(CO)—C₁₋₃-alkyl.

[0029] The compounds of the invention additionally preferably includeN-oxides of the formula 1 in which

[0030] B is an N-oxide group. These are the compounds of the inventionof the formula 1b

[0031] in which

[0032] A is nitrogen,

[0033] R¹

[0034] (i) is —C₁₋₁₀-alkyl, straight-chain or branched-chain, optionallymono- or polysubstituted by —OH, —SH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NHC₆₋₁₄-aryl, —N(C₆₋₁₄-aryl)₂,—N(C₁₋₆-alkyl)(C₆₋₁₄-aryl), —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl,—O—C₆₋₁₄-aryl, —S—C₁₋₆-alkyl, —S—C₆ ₁₄-aryl, —SO₃H, —SO₂C₁₋₆-alkyl,—SO₂C₆₋₁₄-aryl, —OSO₂C₁₋₆-alkyl, —OSO₂C₆₋₁₄-aryl, —COOH, —(CO)C₁₅-alkyl,—COO—C₁₋₅-alkyl —O(CO)C₁₋₅-alkyl, by mono-, bi-or tricyclic saturated ormono- or polyunsaturated carbocycles with 3-14 ring members or/and bymono-, bi- or tricyclic saturated or mono- or polyunsaturatedheterocycles with 5-15 ring members and 1-6 heteroatoms, which arepreferably N, O and S, where the C₆₋₁₄-aryl groups and the carbocyclicand heterocylic substituents in turn may optionally be substituted oneor more times by —C₁₋₆-alkyl, —OH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —SO₃H,—SO₂C₁₋₆-alkyl, —OSO₂C₁₋₆-alkyl, —COOH, —(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkylor/and —O(CO)C₁₋₅-alkyl, and where the alkyl groups on the carbocyclicand heterocyclic substituents in turn may optionally be substituted oneor more times by —OH, —SH, —NH₂, —F, —Cl, —Br, —I, —SO₃H or/and —COOH,or

[0035] (ii) is —C₂₋₁₀-alkenyl, mono- or polyunsaturated, straight-chainor branched-chain,

[0036] optionally mono- or polysubstituted by —OH, —SH, —NH₂,—NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NHC₆₋₁₄-aryl, —N (C₆₋₁₄-aryl)₂,—N(C₁₋₆-alkyl)(C₆₋₁₄-aryl), —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl,—O—C₆₋₁₄-aryl, —S—C₁₋₆-alkyl, —S—C₆₋₁₄-aryl, —SO₃H, —SO₂C₁₋₆-alkyl,—SO₂C₆₋₁₄-aryl, —OSO₂C₁₋₆-alkyl, —OSO₂C₆₋₁₄-aryl, —COOH,—(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl, —O(CO)C₁₋₅-alkyl, by mono-, bi- ortricyclic saturated or mono- or polyunsaturated carbocycles with 3-14ring members or/and by mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles with 5-15 ring members and 1-6 heteroatoms,which are preferably N, O and S, where the C₆₋₁₄-aryl groups and thecarbocyclic and heterocyclic substituents in turn may optionally besubstituted one or more times by —C₁₋₆-alkyl-OH, —NH₂, —NHC₁₋₆-alkyl,—N(C₁₋₆-alkyl)₂, —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —SO₃H, —SO₂C₁₋₆-alkyl, —OSO₂C₁₋₆-alkyl, —COOH,—(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl or/and —O(CO)C₁₋₅-alkyl,

[0037] and where the alkyl groups on the carbocyclic and heterocyclicsubstituents in turn may optionally be substituted one or more times by—OH, —SH, —NH₂, —F, —Cl, —Br, —I, —SO₃H or/and —COOH,

[0038] R² is hydrogen or —C₁₋₃-alkyl,

[0039] R³ and R⁴ may be identical or different and are hydrogen,—C₁₋₆-alkyl, —OH, —SH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NO₂, —CN,—SO₃H, —SO₃—C₁₋₆-alkyl, —COOH, —COO—C₁₋₆-alkyl, —O(CO)—C₁₋₅-alkyl, —F,—Cl, —Br, —I, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, -phenyl or -pyridyl, wherethe phenyl or pyridyl substituents in turn may optionally be substitutedone or more times by —C₁₋₃-alkyl, —OH, —SH, —NH₂, —NHC₁₋₃-alkyl,—N(C₁₋₃-alkyl)₂, —NO₂, —CN, —COOH, —SO₃H, —SO₃C₁₋₃-alkyl,—COOC₁₋₃-alkyl, —F, —Cl, —Br, —I, —O—C₁₋₃-alkyl, —S—C₁₋₃-alkyl or/and—O(CO)—C₁₋₃-alkyl, and where alkyl substituents in turn may optionallybe substituted one or more times by —OH, —SH, —NH₂, —F, —Cl, —Br, —I,—SO₃H, —SO₃C₁₋₃-alkyl, —COOH, —COOC₁₋₃-alkyl, —O—C₁₋₃-alkyl,—S—C₁₋₃-alkyl or/and —O(CO)—C₁₋₃-alkyl.

[0040] The compounds of the invention additionally include N-oxides ofthe formula 1 in which

[0041] A and B are an N-oxide group. These are the compounds of theinvention of the formula 1c

[0042] in which

[0043] R¹

[0044] (i) is —C₁₋₁₀-alkyl, straight-chain or branched-chain, optionallymono- or polysubstituted by —OH, —SH, —NH₂, —NHC₁₋₆-alkyl,—N(C₁₋₆-alkyl)₂, —NHC₆₋₁₄-aryl, —N(C₆₋₁₄-aryl)₂,—N(C₁₋₆-alkyl)(C₆₋₁₄-aryl), —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl,—O—C₆₋₁₄-aryl, —S—C₁₋₆-alkyl, —S—C₆₋₁₄-aryl, —SO₃H, —SO₂C₁₋₆-alkyl,—SO₂C₆₋₁₄-aryl, —OSO₂C₁₋₆-alkyl, —OSO₂C₆₋₁₄-aryl, —COOH, —(CO)C₁₅-alkyl,—COO—C₁₋₅-alkyl, —O(CO)C₁₋₅-alkyl, by mono-, bi- or tricyclic saturatedor mono- or polyunsaturated carbocycles with 3-14 ring members or/and bymono-, bi- or tricyclic saturated or mono- or polyunsaturatedheterocycles with 5-15 ring members and 1-6 heteroatoms, which arepreferably N, O and S, where the C₆₋₁₄-aryl groups and the carbocyclicand heterocyclic substituents in turn may optionally be substituted oneor more times by —C₁₋₆-alkyl, —OH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —SO₃H,—SO₂C₁₋₆-alkyl, —OSO₂C₁₋₆-alkyl, —COOH, —(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkylor/and —O(CO)C₁₋₅-alkyl, and where the alkyl groups on the carbocyclicand heterocyclic substituents in turn may optionally be substituted oneor more times by —OH, —SH, —NH₂, —F, —Cl, —Br, —I, —SO₃H or/and —COOH,or

[0045] (ii) is —C₂₋₁₀-alkenyl, mono- or polyunsaturated, straight-chainor branched-chain, optionally mono- or polysubstituted by —OH, —SH,—NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NHC₆₋₁₄-aryl, —N(C₆₋₁₄-aryl)₂,—N(C₁₋₆-alkyl)(C₆₋₁₄-aryl), —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl,—O—C₆₋₁₄-aryl, —S—C₁₋₆-alkyl, —S—C₆₋₁₄-aryl, —SO₃H, —SO₂C₁₋₆-alkyl,—SO₂C₆₋₁₄-aryl, —OSO₂C₁₋₆-alkyl, —OSO₂C₆₋₁₄-aryl, —COOH,—(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl, —O(CO)C₁₋₅-alkyl, by mono-, bi- ortricyclic saturated or mono- or polyunsaturated carbocycles with 3-14ring members or/and by mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles with 5-15 ring members and 1-6 heteroatoms,which are preferably N, O and S,

[0046] where the C₆₋₁₄-aryl groups and the carbocyclic and heterocyclicsubstituents in turn may optionally be substituted one or more times by—C₁₋₆-alkyl, —OH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NO₂, —CN, —F,—Cl, —Br, —I, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —SO₃H, —SO₂C₁₋₆-alkyl,—OSO₂C₁₋₆-alkyl, —COOH, —(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl or/and—O(CO)C₁₋₅-alkyl, and where the alkyl groups on the carbocyclic andheterocyclic substituents in turn may optionally be substituted one ormore times by —OH, —SH, —NH₂, —F, —Cl, —Br, —I, —SO₃H or/and —COOH,

[0047] R² is hydrogen or —C₁₋₃-alkyl,

[0048] R³ and R⁴ may be identical or different and are hydrogen,—C₁₋₆-alkyl, —OH, —SH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NO₂, —CN,—SO₃H, —SO₃—C₁₋₆-alkyl, —COOH, —COO—C₁₋₆-alkyl, —O(CO)—C₁₋₅-alkyl, —F,—Cl, —Br, —I, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, -phenyl or -pyridyl, wherethe phenyl or pyridyl substituents in turn may optionally be substitutedone or more times by —C₁₋₃-alkyl, —OH, —SH, —NH₂, —NHC₁₋₃-alkyl,—N(C₁₋₃-alkyl)₂, —NO₂, —CN, —SO₃H, —SO₃C₁₋₃-alkyl, —COOH,—COOC₁₋₃-alkyl, —F, —Cl, —Br, —I, —O—C₁₋₃-alkyl, —S—C₁₋₃-alkyl or/and—O(CO)C₁₋₃-alkyl, and where the alkyl substituents in turn mayoptionally be substituted one or more times by —OH, —SH, —NH₂, —F, —Cl,—Br, —I, —SO₃H, —SO₃C₁₋₃-alkyl, —COOH, —COOC₁₋₃-alkyl, —O—C₁₋₃-alkyl,—S—C₁₋₃-alkyl or/and —O(CO)—C₁₋₃-alkyl.

[0049] Preferred compounds of the formula 1 are those in which R¹ is anoptionally substituted C₁₋₄-alkyl radical, particularly preferably a C₁radical, with a cyclic substituent. The cyclic substituents arepreferably C₃₋₈-cycloalkyl groups or C₅₋₁₀-aryl or heteroaryl radicals,e.g. phenyl or naphthyl radicals, which may have at least onesubstituent selected from halogen, i.e. —F, —Cl, —Br or —I, —OH, —NO₂,—CN, —CH₃, —OCH₃ and —CF₃.

[0050] R² is preferably H or —CH₃. At least one of R³ and R⁴ ispreferably halogen, i.e. —F, —Cl, —Br or —I. R³ and R⁴ are particularlypreferably halogen, e.g. —Cl.

[0051] The invention further relates to physiologically tolerated saltsof the compounds of formula 1.

[0052] The physiologically tolerated salts are obtained in aconventional way by neutralizing the bases with inorganic or organicacids or by neutralizing the acids with inorganic or organic bases.Examples of suitable inorganic acids are hydrochloric acid, sulfuricacid, phosphoric acid or hydrobromic acid, and examples of suitableorganic acids are carboxylic or sulfonic acids, such as acetic acid,tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid,maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid,benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamicacid, mandelic acid, citric acid, malic acid, salicylic acid,3-aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid,isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid,ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonicacid, benzenesulfonic acid, 4-methylbenzenesulfonic acid ornaphthalene-2-sulfonic acid. Examples of suitable inorganic bases aresodium hydroxide solution, potassium hydroxide solution, ammonia, andsuitable organic bases are amines, but preferably tertiary amines suchas trimethylamine, triethylamine, pyridine, N,N-dimethylaniline,quinoline, isoquinoline, α-picoline, β-picoline, γ-picoline, quinaldineor pyrimidine.

[0053] Physiologically tolerated salts of the compounds of formula 1 canadditionally be obtained by converting derivatives having tertiary aminogroups in a manner known per se with quaternizing agents into thecorresponding quaternary ammonium salts. Examples of suitablequaternizing agents are alkyl halides such as methyl iodide, ethylbromide and n-propyl chloride, but also arylalkyl halides such as benzylchloride or 2-phenylethyl bromide.

[0054] The invention further relates to the D form, the L form and D,Lmixtures of compounds of the formula 1 which contain an asymmetriccarbon atom, and in the case of a plurality of asymmetric carbon atoms,also the diastereomeric forms. Compounds of the formula 1 which containasymmetric carbon atoms and usually result as racemates can be separatedinto the optically active isomers in a manner known per se, for examplewith an optically active acid. However, it is also possible to employ anoptically active starting substance from the outset, in which case acorresponding optically active or diastereomeric compound is obtained asfinal product.

[0055] The compounds of the invention have been found to havepharmacologically important properties which can be utilized in therapy.The compounds of formula 1 can be employed alone, in combination withone another or in combination with other active ingredients.

[0056] The compounds of the invention are inhibitors ofphosphodiesterase 4. It is therefore an aspect of this invention thatthe compounds of formula 1 and the salts thereof, and pharmaceuticalpreparations which comprise these compounds or salts thereof, can beused for the treatment of disorders in which inhibition ofphosphodiesterase 4 is beneficial.

[0057] These disorders include, for example, inflammations of joints,including arthritis and rheumatoid arthritis, and other arthriticdisorders such as rheumatoid spondylitis and osteoarthritis. Furtherpossible uses are the treatment of patients suffering from osteoporosis,sepsis, septic shock, Gram-negative sepsis, toxic shock syndrome,respiratory distress syndrome, asthma or other chronic pulmonarydisorders, bone resorption disorders or transplant rejection reactionsor other autoimmune diseases such as lupus erythematosus, multiplesclerosis, glomerulonephritis and uveitis, insulin-dependent diabetesmellitus and chronic demyelinization.

[0058] The compounds of the invention can additionally be employed forthe therapy of infections such as viral infections and parasiticinfections, for example for the therapy of malaria, leishmaniasis,infection-related fever, infection-related muscle pain, AIDS andcachexia, and of non-allergic rhinitis.

[0059] The compounds of the invention can likewise be used for thetherapy of hyperproliferative disorders, in particular of cancers, forexample for the therapy of melanomas, of breast cancer, lung cancer,bowel cancer, skin cancer and of leukemias.

[0060] The compounds of the invention can also be employed asbronchodilators and for the treatment of asthma, e.g. for asthmaprophylaxis.

[0061] The compounds of formula 1 are in addition inhibitors of theaccumulation of eosinophils and the activity thereof. Accordingly, thecompounds of the invention can also be employed for disorders in whicheosinophils are involved. These disorders include, for example,inflammatory respiratory tract disorders such as bronchial asthma,allergic rhinitis, allergic conjuctivitis, atopic dermatitis, eczemas,allergic angiitis, eosinophil-mediated inflammations such aseosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome(pulmonary infiltration with eosinophilia), urticaria, ulcerativecolitis, Crohn's disease and proliferative skin disorders such aspsoriasis or keratosis.

[0062] It is an aspect of this invention that the compounds of formula 1and salts thereof are also able to inhibit LPS-induced pulmonaryneutrophilic infiltration in rats in vivo. The pharmacologicallysignificant properties which have been found prove that the compounds offormula 1 and salts thereof, and pharmaceutical preparations whichcomprise these compounds or salts thereof, can be utilizedtherapeutically for the treatment of chronic obstructive pulmonarydiseases.

[0063] The compounds of the invention additionally have neuroprotectiveproperties and can be used for the therapy of diseases in whichneuroprotection is beneficial. Examples of such disorders are seniledementia (Alzheimer's disease), memory loss, Parkinson's disease,depression, strokes and intermittent claudication.

[0064] Further possible uses of the compounds of the invention are theprophylaxis and therapy of prostate disorders such as, for example,benign prostate hyperplasia, polyuria, nocturia, and the treatment ofincontinence, of colic induced by urinary calculi, and of male andfemale sexual dysfunctions.

[0065] Finally, the compounds of the invention can likewise be used toinhibit the development of drug dependence on repeated use of analgesicssuch as, for example, morphine, and to reduce the development oftolerance on repeated use of these analgesics.

[0066] The drug products are produced by using an effective dose of thecompounds of the invention or salts thereof, in addition to conventionaladjuvants, carriers and additives. The dosage of the active ingredientsmay vary depending on the route of administration, age and weight of thepatient, nature and severity of the disorders to be treated and similarfactors. The daily dose may be given as a single dose to be administeredonce a day, or divided into 2 or more daily doses, and is usually0.001-100 mg. Daily dosages of 0.1-50 mg are particularly preferablyadministered.

[0067] Oral, parenteral, intravenous, transdermal, topical, inhalationaland intranasal preparations are suitable as administration form.Topical, inhalational and intranasal preparations of the compounds ofthe invention are particularly preferably used. Galenical pharmaceuticalpresentations such as tablets, coated tablets, capsules, dispersiblepowders, granules, aqueous solutions, aqueous or oily suspensions,syrup, solutions or drops are used.

[0068] Solid drug forms may comprise inert ingredients and carriers suchas, for example, calcium carbonate, calcium phosphate, sodium phosphate,lactose, starch, mannitol, alginates, gelatin, guar gum, magnesiumstearate or aluminum stearate, methylcellulose, talc, colloidal silicas,silicone oil, high molecular weight fatty acids (such as stearic acid),agar-agar or vegetable or animal fats and oils, solid high molecularweight polymers (such as polyethylene glycol); preparations suitable fororal administration may, if desired, comprise additional flavoringsand/or sweeteners.

[0069] Liquid drug forms can be sterilized and/or where appropriatecomprise excipients such as preservatives, stabilizers, wetting agents,penetrants, emulsifiers, spreading agents, solubilizers, salts, sugarsor sugar alcohols to control the osmotic pressure or for bufferingand/or viscosity regulators.

[0070] Examples of such additions are tartrate buffer and citratebuffer, ethanol, complexing agents (such as ethylenediaminetetraaceticacid and its non-toxic salts). Suitable for controling the viscosity arehigh molecular weight polymers such as, for example, liquid polyethyleneoxide, microcrystalline celluloses, carboxymethylcelluloses,polyvinylpyrrolidones, dextrans or gelatin. Examples of solid carriersare starch, lactose, mannitol, methylcellulose, talc, colloidal silicas,higher molecular weight fatty acids (such as stearic acid), gelatin,agar-agar, calcium phosphate, magnesium stearate, animal and vegetablefats, solid high molecular weight polymers such as polyethylene glycol.

[0071] Oily suspensions for parenteral or topical uses may be vegetablesynthetic or semisynthetic oils such as, for example, liquid fatty acidesters with in each case 8 to 22 C atoms in the fatty acid chains, forexample palmitic, lauric, tridecylic, margaric, stearic, arachic,myristic, behenic, pentadecylic, linoleic, elaidic, brasidic, erucic oroleic acid, which are esterified with monohydric to trihydric alcoholshaving 1 to 6 C atoms, such as, for example, methanol, ethanol,propanol, butanol, pentanol or isomers thereof, glycol or glycerol.Examples of such fatty acid esters are commercially available miglyols,isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG6-capric acid, caprylic/capric esters of saturated fatty alcohols,polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acidesters such as artificial duck preen gland fat, coco fatty acidisopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutylphthalate, diisopropyl adipate, polyol fatty acid esters inter alia.Likewise suitable are silicone oils differing in viscosity or fattyalcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearylalcohol or oleyl alcohol, fatty acids such as, for example, oleic acid.It is additionally possible to use vegetable oils such as castor oil,almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybeanoil.

[0072] Suitable solvents, gel formers and solubilizers are water orwater-miscible solvents. Suitable examples are alcohols such as, forexample, ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol,polyethylene glycols, phthalates, adipates, propylene glycol, glycerol,di- or tripropylene glycol, waxes, methyl Cellosolve, Cellosolve,esters, morpholines, dioxane, dimethyl sulfoxide, dimethylformamide,tetrahydrofuran, cyclohexanone etc.

[0073] Film formers which can be used are cellulose ethers able todissolve or swell both in water and in organic solvents, such as, forexample, hydroxypropylmethylcellulose, methylcellulose, ethylcelluloseor soluble starches.

[0074] Combined forms of gel formers and film formers are likewiseperfectly possible. Ionic macromolecules are used in particular for thispurpose, such as, for example, sodium carboxymethylcellulose,polyacrylic acid, polymethacrylic acid and salts thereof, sodiumamylopectin semiglycolate, alginic acid or propylene glycol alginate assodium salt, gum arabic, xanthan gum, guar gum or carrageenan.

[0075] Further formulation aids which can be employed are: glycerol,paraffin of differing viscosity, triethanolamine, collagen, allantoin,novantisolic acid.

[0076] It may also be necessary to use surfactants, emulsifiers orwetting agents for the formulation, such as, for example, Na laurylsulfate, fatty alcohol ether sulfates,di-Na-N-lauryl-β-iminodipropionate, polyethoxylated castor oil orsorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween),cetyl alcohol, lecithin, glyceryl monostearate, polyoxyethylenestearate, alkylphenol polyglycol ether, cetyltrimethylammonium chlorideor mono/dialkylpolyglycol ether orthophosphoric acid monoethanolaminesalts.

[0077] Stabilizers such as montmorillonites or colloidal silicas tostabilize emulsions or to prevent degradation of the active substances,such as antioxidants, for example tocopherols or butylatedhydroxyanisole, or preservatives such as p-hydroxybenzoic esters, maylikewise be necessary where appropriate to prepare the desiredformulations.

[0078] Preparations for parenteral administration may be present inseparate dose unit forms such as, for example, ampoules or vials.Solutions of the active ingredient are preferably used, preferablyaqueous solutions and especially isotonic solutions, but alsosuspensions. These injection forms can be made available as finishedproduct or be prepared only immediately before use by mixing the activecompound, e.g. the lyophilisate, where appropriate with further solidcarriers, with the desired solvent or suspending agent.

[0079] Intranasal preparations may be in the form of aqueous or oilysolutions or of aqueous or oily suspensions. They may also be in theform of lyophilisates which are prepared before use with the suitablesolvent or suspending agent.

[0080] The manufacture, bottling and closure of the products takes placeunder the usual antimicrobial and aseptic conditions.

[0081] The invention further relates to processes for preparing thecompounds of the invention.

[0082] The compounds of the general formula 1 with the meanings of A, B,R¹, R², R³ and R⁴ described above are prepared according to theinvention

[0083] by oxidizing compounds of the formula 1 with the meaning of R¹,R², R³ and R⁴ described above, in which A is nitrogen and B may benitrogen or carbon, in a manner known per se by treatment with anoxidizing agent, e.g. an organic peracid, preferably withm-chloroperbenzoic acid or/and peracetic acid, to the compounds of theinvention of the formula 1a, 1b or 1c. Mixtures of N-oxides which resultwhere appropriate can be separated in a manner known per se bycrystallization or chromatographic methods into the pure compounds ofthe formula 1a, 1b or 1c.

EXAMPLES Example 1 Exemplary Process for Preparing Compounds of theInvention of the Formula 1a

[0084] 1.1N-(3,5-Dichloropyridin-4-yl)-[1-(4-fluorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide

[0085] 3 g ofN-(3,5-dichloropyridin-4-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]glyoxylamideare dissolved in 180 ml of dichloromethane. While stirring, a solutionof 6 g of m-chloroperbenzoic acid in 12 ml of acetic acid is addeddropwise. The reaction mixture is stirred at room temperature for 7days. The mixture is adjusted to pH 8 to 9 by adding a potassiumcarbonate solution. The phases are separated, and the organic phase iswashed with 100 ml of water. The solvent is distilled out in vacuo. Theresidue is stirred with 10 ml of isopropanol. The crystals are removedand dried at room temperature. The crude product is purified bypreparative HPLC. A mixture of ethyl acetate with methanol in the ratio85:15 is used as solvent system.

[0086] The solvent mixture is distilled from the product-containingfraction in vacuo, and the residue is recrystallized from isopropanol.

[0087] Yield: 0.3 g (9.4% of theory)

[0088] Melting point: 205-208° C.

[0089] 1.2N-(2,6-Dichlorophenyl)-[1-(2-chlorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide

[0090] 3.1 g ofN-(3,5-dichlorophenyl)-[1-(2-chlorobenzyl)-7-azaindol-3-yl]glyoxylamideare dissolved in 180 ml of dichloromethane. While stirring, a solutionof 6 g of m-chloroperbenzoic acid in 12 ml of acetic acid is addeddropwise. The reaction mixture is stirred at room temperature for 7days. The mixture is adjusted to pH 8 to 9 by adding a potassiumcarbonate solution. The phases are separated, and the organic phase iswashed with 100 ml of water. The solvent is distilled out in vacuo. Theresidue is stirred with 30 ml of water at 50° C., filtered off withsuction and recrystallized from 100 ml of isopropanol.

[0091] Yield: 1.3 g (40% of theory)

[0092] Melting point: 165-168° C.

Example 2 Exemplary Process for Preparing Compounds of the Invention ofthe Formula 1b

[0093] 2.1N-(3,5-Dichloro-1-oxopyridin-4-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]glyoxylamide

[0094] 3 g ofN-(3,5-dichloropyridin-4-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]glyoxylamideare dissolved in 180 ml of dichloromethane. While stirring, a solutionof 6 g of m-chloroperbenzoic acid in 12 ml of acetic acid is addeddropwise. The reaction mixture is stirred at room temperature for 7days. The mixture is adjusted to pH 8 to 9 by adding a potassiumcarbonate solution. The phases are separated, and the organic phase iswashed with 100 ml of water. The solvent is distilled out in vacuo. Theresidue is stirred with 10 ml of isopropanol. The crystals are removedand dried at room temperature. The crude product is purified bypreparative HPLC. A mixture of ethyl acetate with methanol in the ratio85:15 is used as solvent system.

[0095] The solvent mixture is distilled from the product-containingfraction in vacuo, and the residue is recrystallized from ethanol.

[0096] Yield: 1.2 g (37.5% of theory)

[0097] Melting point: 233-236° C.

Example 3 Exemplary Process for Preparing Compounds of the Invention ofthe Formula 1c

[0098] 3.1N-(3,5-Dichloro-1-oxopyridin-4-yl)-[1-(4-fluorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide

[0099] 3 g ofN-(3,5-dichloropyridin-4-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]glyoxylamideare dissolved in 180 ml of dichloromethane. While stirring, a solutionof 6 g of m-chloroperbenzoic acid in 12 ml of acetic acid is addeddropwise. The reaction mixture is stirred at room temperature for 7days. The mixture is adjusted to pH 8 to 9 by adding a potassiumcarbonate solution. The phases are separated, and the organic phase iswashed with 100 ml of water. The solvent is distilled out in vacuo. Theresidue is stirred with 10 ml of isopropanol. The crystals are removedand dried at room temperature. The crude product is purified bypreparative HPLC. A mixture of ethyl acetate with methanol in the ratio90:10 is used as solvent system.

[0100] The solvent mixture is distilled from the product-containingfraction in vacuo, and the residue is recrystallized from ethanol.

[0101] Yield: 0.2 g (6.3% of theory)

[0102] Melting point: 254-257° C.

Example 4 Preparation of Further Compounds

[0103] Numerous further compounds of the formula 1 can be prepared byusing the indicated processes for preparation, of which the followingare cited as examples: (1)

Com- pound A B R¹ —R² —R³ —R⁴ 1 N—O N 4-Fluorobenzyl- —H —Cl —Cl 2 N—OCH 2-Chlorobenzyl- —H —Cl —Cl 3 N N—O 4-Fluorobenzyl- —H —Cl —Cl 4 N—ON—O 4-Fluorobenzyl- —H —Cl —Cl 5 N—O CH 4-Fluorobenzyl- —H —H —H 6 N N—O2-Fluorobenzyl- —H —Cl —Cl 7 N N—O 3-Nitrobenzyl- —H —Cl —Cl 8 N N—O2,6-Difluorobenzyl- —H —Cl —Cl 9 N N—O 2,4-Dichlorobenzyl- —H —Cl —Cl 10N—O N 2,4-Dichlorobenzyl- —H —Cl —Cl 11 N N—O 2-Chlorobenzyl- —H —Cl —Cl12 N—O N 2-Chlorobenzyl- —H —Cl —Cl 13 N—O N—O 2-Chlorobenzyl- —H —Cl—Cl 14 N—O N 2-Chlorobenzyl- —CH₃ —Cl —Cl 15 N N—O 2-Chlorobenzyl- —CH₃—Cl —Cl 16 N N—O 2-Chlorobenzyl- —CH₃ —H —H 17 N N—O 2,6-Dichlorobenzyl-—H —Cl —Cl 18 N N—O 2-Methylbenzyl- —H —Cl —Cl 19 N N—O2,6-Dimethylbenzyl- —H —Cl —Cl 20 N N—O n-Hexyl- —H —Cl —Cl 21 N N—OIsobutyl- —H —Cl —Cl 22 N N—O Cyclopropylmethyl- —H —Cl —Cl 23 N N—O1-Naphthylmethyl- —H —Cl —Cl 24 N—O N 2-Chloro-6- —H —Cl —Clfluorobenzyl 25 N N—O 2-Chloro-6- —H —Cl —Cl fluorobenzyl- 26 N—O N—O2-Chloro-6- —H —Cl —Cl fluorobenzyl- 27 N N—O 2-Difluoromethoxy- —H —Cl—Cl benzyl- 28 N N—O 2-Cyanobenzyl- —H —Cl —Cl

[0104] The compounds of the invention are strong inhibitors ofphosphodiesterase 4. Their therapeutic potential is demonstrated in vivofor example through the inhibition the asthmatic late-phase reaction(eosinophilia) and through the inhibition of LPS-induced neutrophilia inrats.

Example 5 Phosphodiesterase 4 Inhibition

[0105] PDE4 activity is determined using enzyme preparations from humanpolymorphonuclear lymphocytes (PMNL). Human blood (buffy coats) wasanticoagulated with citrate. A centrifugation at 700×g at roomtemperature (RT) for 20 minutes separates the platelet-rich plasma inthe supernatant from the erythrocytes and leukocytes. The PMNLs for thePDE4 determination are isolated by a subsequent dextran sedimentationand in gradient centrifugation with Ficoll-Paque. After the cells havebeen washed twice, the erythrocytes which are still present are lysed byadding 10 ml of hypotonic buffer (155 mM NH₄Cl, 10 mM NaHCO₃, 0.1 mMEDTA, pH=7.4) at 4° C. within 6 minutes. The still intact PMNLs are thenwashed twice with PBS and lysed by ultrasound. The supernatant from acentrifugation at 4° C. and 48000×g for one hour contains the cytosolicfraction of PDE 4 and is employed for the PDE4 measurements.

[0106] The phosphodiesterase activity is assayed using a modifiedAmersham Pharmacia Biotech method, an SPA (scintillation proximityassay).

[0107] The reaction mixtures contain buffer (50 mM Tris-HCl (pH 7.4), 5mM MgCl₂, 100 μM cGMP), the inhibitors in variable concentrations andthe appropriate enzyme preparation. The reaction is started by addingthe substrate, 0.5 μM [³H]-cAMP. The final volume is 100 μl. Testsubstances are made up as stock solutions in DMSO. The DMSOconcentration in the reaction mixture is 1% v/v. The PDE activity isunaffected at this DMSO concentration. After the reaction has beenstarted by adding substrate, the samples are incubated at 37° C. for 30minutes. The reaction is stopped by adding a defined amount of SPAbeads, and the samples are counted after one hour in a Beta counter. Thenonspecific enzymic activity (the blank) is determined in the presenceof 100 μM rolipram and subtracted from the test results. The incubationmixtures for the PDE4 assay contain 100 μM cGMP in order to inhibit anycontamination by PDE 3.

[0108] The IC₅₀ values for inhibition of phosphodiesterase 4 determinedfor the compounds of the invention were in the range from 10⁻¹⁰ to 10⁻⁵M. The selectivity factor in relation to PDE of types 3, 5 and 7 is from100 to 10,000

[0109] The results of PDE4 inhibition for selected use examples arecompiled by way of example in the following table: PDE 4 inhibitionCompound IC₅₀ [μmol/l] 1 0.052 2 0.048 3 0.008 4 0.751

Example 6 Inhibition of Late-Phase Eosinophilia 48 h After InhalationalOvalbumin Challenge in Actively Sensitized Brown Norway Rats

[0110] Inhibition of the pulmonary eosinophilic infiltration by thesubstances of the invention is tested on male brown Norway rats (200-250g) actively sensitized against ovalbumin (OVA). The sensitization takesplace by subcutaneous injections of a suspension of 10 μg of OVAtogether with 20 mg of aluminum hydroxide as adjuvant in 0.5 ml ofphysiological saline per animal on day 1, 14 and 21. In addition tothis, the animals receive at the same time i.p. injections of 0.25 ml ofBordetella pertussis vaccine dilution per animal. On day 28 of the test,the animals are placed singly in open 1 l Plexiglas boxes connected to ahead/nose exposure apparatus. The animals are exposed to an aerosol of1.0% ovalbumin suspension (allergen challenge). The ovalbumin aerosol isgenerated by a nebulizer (Bird micro nebulizer, Palm Springs Calif.,USA) operated with compressed air (0.2 MPa). The exposure time is 1hour, with an aerosol of 0.9% saline being nebulized for normal controlslikewise for 1 hour.

[0111] 48 hours after the allergen challenge there is a massivemigration of eosinophilic granulocytes into the lungs of the animals. Atthis time, the animals are anesthetized with an overdose ofethylurethane (1.5 g/kg of body weight i.p.), and a bronchoalveolarlavage (BAL) is carried out with 3×4 ml of Hank's balanced solution. Thetotal cell count and the number of eosinophilic granulocytes in thepooled BAL liquid are subsequently determined using an automatic celldifferentiation instrument (Bayer Diagnostics Technicon H1E). Theeosinophils (EOS) in the BAL are calculated for each animal in10⁶/animal: EOS/μl×BAL recovery (ml)=EOS/animal.

[0112] Two control groups (nebulization of physiological saline andnebulization of OVA solution) are included in each test.

[0113] The percentage inhibition of the eosinophilia in the test grouptreated with the substance is calculated by the following formula:

{((OVAC−SC)−(OVAD−SC))/(OVAC−SC)}×100%=% inhibition

[0114] (SC=control group treated with vehicle and challenged with 0.9%saline; OVAC=control group treated with vehicle and challenged with 1%ovalbumin suspension; OVAD=test group treated with substance andchallenged with 1% ovalbumin suspension)

[0115] The test substances are administered intraperitoneally or orallyas suspension in 10% polyethylene glycol 300 and 0.5%5-hydroxyethylcellulose 2 hours before the allergen challenge. Thecontrol groups are treated with the vehicle in accordance with the testsubstance application form.

[0116] The compounds of the invention inhibit the late-phaseeosinophilia by 30% to 100% after intraperitoneal administration of 10mg/kg and by 30% to 80% after oral administration of 30 mg/kg.

[0117] The compounds of the invention are thus particularly suitable forproducing drug products for the treatment of disorders associated withthe effect of eosinophils.

Example 7 Inhibition of Lipopolysaccharide (LPS)-Induced PulmonaryNeutrophilia in Lewis Rats

[0118] The inhibition of pulmonary neutrophil infiltration by thesubstances of the invention is tested on male Lewis rats (250-350 g) .On the day of the test, the animals are placed singly in open 1 lPlexiglas boxes connected to a head/nose exposure apparatus. The animalsare exposed to an aerosol from a lipopolysaccharide suspension (100 μgof LPS/ml of 0.1% hydroxylamine solution) in PBS (LSP provocation). TheLPS/hydroxylamine aerosol is generated by a nebulizer (Bird micronebulizer, Palm Springs Calif., USA) operated by compressed air (0.2MPa). The exposure time is 40 minutes, with an aerosol being nebulizedfrom 0.1% hydroxylamine solution in PBS for normal controls, likewisefor 40 minutes.

[0119] 6 hours after the LPS provocation there is a maximal, massivemigration of neutrophilic granulocytes into the lungs of the animals. Atthis time, the animals are anesthetized with an overdose ofethylurethane (1.5 g/kg of body weight i.p.), and a bronchoalveolarlavage (BAL) is carried out with 3×4 ml of Hank's balanced solution. Thetotal cell count and the number of neutrophilic granulocytes in thepooled BAL liquid are subsequently determined using an automatic celldifferentiation apparatus (Bayer Diagnostics Technicon H1E). Theneutrophils (NEUTRO) in the BAL are calculated for each animal in10⁶/animal: NEUTRO/μl×BAL recovery (ml)=NEUTRO/animal.

[0120] Two control groups (nebulization of 0.1% hydroxylamine solutionin PBS and nebulization of 100 μg of LPS/ml of 0.1% hydroxylaminesolution in PBS) are included in each test.

[0121] The percentage inhibition of the neutrophilia in the test grouptreated with the substance is calculated by the following formula:

{((LPSC−SC)−(LPSD−SC))/(LPSC−SC)}×100%=% inhibition

[0122] SC=control group treated with vehicle and challenged with 0.1%hydroxylamine solution; LPSC=control group treated with vehicle andchallenged with LPS (100 μg/ml of 0.1% hydroxylamine solution);LPSD=test group treated with substance and challenged with LPS (100μg/ml of 0.1% hydroxylamine solution).

[0123] The test substances are administered orally as suspension in 10%polyethylene glycol 300 and 0.5% 5-hydroxyethylcellulose 2 hours beforethe LPS provocation. The control groups are treated with the vehicle inaccordance with the test substance administration form.

[0124] The compounds of the invention inhibit the neutrophilia by 30% to90% after oral administration of 1 mg/kg and are thus particularlysuitable for producing drug products for the treatment of disordersassociated with the effect of neutrophils.

1. A compound of formula 1

in which A may be nitrogen or an N-oxide group, B may be carbon,nitrogen or an N-oxide group, R¹ (i) is —C₁₋₁₀-alkyl, straight-chain orbranched-chain, optionally mono- or polysubstituted by —OH, —SH, —NH₂,—NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NHC₆₋₁₄-aryl, —N(C₆₋₁₄-aryl)₂,—N(C₁₋₆-alkyl)(C₆₋₁₄-aryl), —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl,—O—C₆₋₁₄-aryl, —S—C₁₋₆-alkyl, —S—C₆₋₁₄-aryl, —SO₃H, —SO₂C₁₋₆-alkyl,—SO₂C₆₋₁₄-aryl, —OSO₂C₁₋₆-alkyl, —OSO₂C₆₋₁₄-aryl, —COOH,—(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl, —O(CO)C₁₋₅-alkyl, by mono-, bi- ortricyclic saturated or mono- or polyunsaturated carbocycles with 3-14ring members or/and by mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles with 5-15 ring members and 1-6 heteroatoms,which are preferably N, O and S, where the C₆₋₁₄-aryl groups and thecarbocyclic and heterocyclic substituents in turn may optionally besubstituted one or more times by —C₁₋₆-alkyl, —OH, —NH₂, —NHC₁₋₆-alkyl,—N(C₁₋₆-alkyl)₂, —NO₂, —CN, —F, —Cl, —Br, —I, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —SO₃H, —SO₂C₁₋₆-alkyl, —OSO₂C₁₋₆-alkyl, —COOH,—(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl or/and —O(CO)C₁₋₅-alkyl, and where thealkyl groups on the carbocyclic and heterocyclic substituents in turnmay optionally be substituted one or more times by —OH, —SH, —NH₂, —F,—Cl, —Br, —I, —SO₃H or/and —COOH, or (ii)is —C₂₋₁₀-alkenyl, mono- orpolyunsaturated, straight-chain or branched-chain, optionally mono- orpolysubstituted by —OH, —SH, —NH₂, —NHC₁₋₆—alkyl, —N(C₁₋₆-alkyl)₂,—NHC₆₋₁₄-aryl, —N(C₆₋₁₄-aryl)₂, —N(C₁₋₆-alkyl)(C₆₋₁₄-aryl), —NO₂, —CN,—F, —Cl, —Br, —I, —O—C₁₋₆-alkyl, —O—C₆₋₁₄-aryl, —S—C₁₋₆-alkyl,—S—C₆₋₁₄-aryl, —SO₃H, —SO₂C₁₋₆-alkyl, —SO₂C₆₋₁₄-aryl, —OSO₂C₁₋₆-alkyl,—OSO₂C₆₋₁₄-aryl, —COOH, —(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl,—O(CO)C₁₋₅-alkyl, by mono-, bi- or tricyclic saturated or mono- orpolyunsaturated carbocycles with 3-14 ring members or/and by mono-, bi-or tricyclic saturated or mono- or polyunsaturated heterocycles with5-15 ring members and 1-6 heteroatoms, which are preferably N, O and S,where the C₆₋₁₄-aryl groups and the carbocyclic and heterocyclicsubstituents in turn may optionally be substituted one or more times by—C₁₋₆-alkyl, —OH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NO₂, —CN, —F,—Cl, —Br, —I, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —SO₃H, —SO₂C₁₋₆-alkyl,—OSO₂C₁₋₆-alkyl, —COOH, —(CO)C₁₋₅-alkyl, —COO—C₁₋₅-alkyl or/and —O(CO)C₁₋₅-alkyl, and where the alkyl groups on the carbocyclic and heterocylicsubstituents in turn may optionally be substituted one or more times by—OH, —SH, —NH₂, —F, —Cl, —Br, —I, —SO₃H or/and —COOH, R² is hydrogen or—C₁₋₃-alkyl, R³ and R⁴ may be identical or different and are hydrogen,—C₁₋₆-alkyl, —OH, —SH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —NO₂, —CN,—SO₃H, —SO₃—C₁₋₆-alkyl, —COOH, —COO—C₁₋₆-alkyl, —O(CO)—C₁₋₅-alkyl, —F,—Cl, —Br, —I, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, -phenyl or -pyridyl, wherethe phenyl or pyridyl substituents in turn may optionally be substitutedone or more times by —C₁₋₃-alkyl, —OH, —SH, —NH₂, —NHC₁₋₃-alkyl,—N(C₁₋₃-alkyl)₂, —NO₂, —CN, —SO₃H, —SO₃C₁₋₃-alkyl, —COOH,—COOC₁₋₃-alkyl, —F, —Cl, —Br, —I, —O—C₁₋₃-alkyl, —S—C₁₋₃-alkyl, or/and—O(CO)C₁₋₃-alkyl, and where the alkyl substituents in turn mayoptionally be substituted one or more times by —OH, —SH, —NH₂, —F, —Cl,—Br, —I, —SO₃H, —SO₃C₁₋₃-alkyl, —COOH, —COOC₁₋₃-alkyl, —O—C₁₋₃-alkyl,—S—C₁₋₃-alkyl or/and —O(CO)—C₁₋₃-alkyl, or salts of the compounds offormula
 1. 2. A compound as claimed in claim 1 having at least oneasymmetric carbon atom in the D form, the L form and D,L mixtures, andin the case of a plurality of asymmetric carbon atoms also thediastereomeric forms.
 3. A compound as claimed in claim 1, wherein A isN and B is N—O.
 4. A compound as claimed in claim 3, wherein R² is —H or—CH₃.
 5. A compound as claimed in claim 4, wherein at least one of R³and R⁴ is in each case a halogen atom.
 6. A compound as claimed in claim1, wherein A is N—O and B is CH, CR³ or N.
 7. A compound as claimed inclaim 6, wherein R² is —H or —CH₃.
 8. A compound as claimed in claim 7,wherein at least one of R³ and R⁴ is in each case a halogen atom.
 9. Acompound as claimed in claim 1 selected from the group consisting of:N-(3,5-dichloropyridin-4-yl)-[1-(4-fluorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide;N-(2,6-dichlorophenyl)-[1-(2-chlorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(4-fluorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide;N-phenyl-[1-(4-fluorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2-fluorobenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(3-nitrobenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2,6-difluorobenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2,4-dichlorobenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloropyridin-4-yl)-[1-(2,4-dichlorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2-chlorobenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloropyridin-4-yl)-[1-(2-chlorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2-chlorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloropyridin-4-yl)-N-methyl-[1-(2-chlorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-N-methyl-[1-(2-chlorobenzyl)-7-azaindol-3-yl]glyoxylamide;N-methyl-N-(1-oxopyridin-4-yl)-[1-(2-chlorobenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2,6-dichlorobenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2-methylbenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2,6-dimethylbenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-(1-hexyl-7-azaindol-3-yl)glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-(1-isobutyl-7-azaindol-3-yl)glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-(1-cyclopropylmethyl-7-azaindol-3-yl)glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-naphth-1-yl-methyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloropyridin-4-yl)-[1-(2-chloro-6-fluorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2-chloro-6-fluorobenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2-chloro-6-fluorobenzyl)-7-oxo-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2-difluoromethylbenzyl)-7-azaindol-3-yl]glyoxylamide;N-(3,5-dichloro-1-oxopyridin-4-yl)-[1-(2-cyanobenzyl)-7-azaindol-3-yl]glyoxylamide;and physiologically tolerated salts thereof.
 10. A process for preparinga compound according to claim 1, wherein compounds in which A isnitrogen and B can be nitrogen or carbon are oxidised by treatment withan oxidizing agent to the compounds of the invention of the formula 1a.


11. The process as claimed in claim 10, wherein said oxidizing agent isselected from the group consisting of a peracid and a peracetic acid.12. The process as claimed in claim 10, wherein resulting mixtures ofN-oxides are fractionated into the pure compounds of the formula 1a, 1bor 1c by crystallization or chromatographic methods.
 13. The process asclaimed in claim 12, wherein mixtures of the solvents ethyl acetate andmethanol, preferably in mixing ratios between 50:50 and 99:1, are usedfor separating mixtures of N-oxides by chromatographic methods.
 14. Amethod of treating disorders in which inhibition of phosphodiesterase 4is therapeutically beneficial in a patient comprising administering atherapeutically effective amount of a compound of claim 1 to a patientin need thereof to inhibit phosphodiesterase
 4. 15. A method of treatingdisorders associated with the effect of eosinophils in a patientcomprising administering a therapeutically effective amount of acompound of claim 1 to a patient in need thereof.
 16. A method oftreating disorders associated with the effect of neutrophils in apatient comprising administering a therapeutically effective amount of acompound of claim 1 to a patient in need thereof.
 17. A method oftreating hyperproliferative disorders in a patient comprisingadministering to said patient a therapeutically effective amount of acompound according to claim 1 to treat the hyperproliferative disorder.18. A drug product comprising a compound according to claim 1 and atleast one of a conventional physiologically tolerated carrier, diluentor excipient.
 19. A process for producing a drug product as claimed inclaim 18, comprising admixing said compound with said carrier, diluentor excipient to form the drug product.
 20. A pharmaceutical compositioncomprising a compound of claim 1 and at least one other activepharmaceutical agent.
 21. The process as claimed in claim 10, whereinsaid oxidizing agent is m-chloroperbenzoic acid.